Effect of Crestor on Lipoprotein Metabolism in Humans
| Status: | Completed |
|---|---|
| Conditions: | High Cholesterol |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 50 - 75 |
| Updated: | 6/21/2017 |
| Start Date: | January 2005 |
| End Date: | February 2006 |
Effect of Crestor on the Kinetics of Plasma Apolipoproteins: Dose-Response Study
The objective of this research is to understand how Crestor can effectively reduce the
levels of the bad cholesterol, LDL, in blood. It is hypothesized that with a low dose,
Crestor will facilitate the rate of removal of LDL from the blood. At the higher dose, the
increased potency of Crestor is explained by a reduction in the production of LDL by the
liver.
levels of the bad cholesterol, LDL, in blood. It is hypothesized that with a low dose,
Crestor will facilitate the rate of removal of LDL from the blood. At the higher dose, the
increased potency of Crestor is explained by a reduction in the production of LDL by the
liver.
Crestor has been demonstrated to be effective in reducing plasma LDL by 20 to 60% in a dose
dependent fashion. While the primary mechanism of action of this class of agents is the
increase in the expression of LDL receptor resulting in accelerated clearance of LDL, the
increase potency of Crestor in comparison to other statins may suggest other mechanisms. We
propose to study the rate of incorporation of deuterated labeled leucine into VLDL apoB and
LDL apoB and to determine the effect of two doses of Crestor (5 mg/day and 40 mg/day) on the
production and clearance of apoB. Participants will be admitted to the General Clinical
Research Center on three occasions (4 days, 3 nights per admission) for these metabolic
studies. This is an open-label study design to reflect usual care with the first admission
taking place while the participant is not on any lipid-lowering therapy. The second
admission will occur after a minimum of 6 weeks on the low dose (5mg/day). The dose will be
increased to 40 mg/day at the time of discharge and the third admission will occur after a
minimum of 6 weeks on the higher dose.
A secondary objective of this study is to examine the rate of production and clearance of
apoA-I, the major protein in HDL, at the 2 doses of Crestor. In addition to a reduction in
LDL, Crestor has also been reported to result in a characteristic dose-dependent increase in
HDL. The mechanism of this increase is not understood.
dependent fashion. While the primary mechanism of action of this class of agents is the
increase in the expression of LDL receptor resulting in accelerated clearance of LDL, the
increase potency of Crestor in comparison to other statins may suggest other mechanisms. We
propose to study the rate of incorporation of deuterated labeled leucine into VLDL apoB and
LDL apoB and to determine the effect of two doses of Crestor (5 mg/day and 40 mg/day) on the
production and clearance of apoB. Participants will be admitted to the General Clinical
Research Center on three occasions (4 days, 3 nights per admission) for these metabolic
studies. This is an open-label study design to reflect usual care with the first admission
taking place while the participant is not on any lipid-lowering therapy. The second
admission will occur after a minimum of 6 weeks on the low dose (5mg/day). The dose will be
increased to 40 mg/day at the time of discharge and the third admission will occur after a
minimum of 6 weeks on the higher dose.
A secondary objective of this study is to examine the rate of production and clearance of
apoA-I, the major protein in HDL, at the 2 doses of Crestor. In addition to a reduction in
LDL, Crestor has also been reported to result in a characteristic dose-dependent increase in
HDL. The mechanism of this increase is not understood.
Inclusion Criteria:
- TG between 200 and 400 mg/dL
- LDLc between 160 and 250 mg/dL
- HDLc between 30 and 50 mg/dL for men and 40-65 mg/dL for women
- Lp(a) less than 30 mg/dL
- Age between 50 and 75 years
Exclusion Criteria:
- current lipid-lowering therapy,
- primary hypertriglyceridemia (TG>400 mg/dL),
- High HDL (HDL>70),
- high Lp(a), greater than 30 mg/dL
- presence of beta-VLDL on agarose electrophoresis,
- current use of immunosuppressive agents,
- hormone replacement therapy for women
- history of cancer, active liver disease or hepatic dysfunction (AST or ALT 1.5 x ULN
(Upper Limit of Normal),
- excessive consumption of alcohol, and recent history of drug abuse.
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